This application is in response to NOT-OD-09-058, "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications." Studies supported by the parent grant address fundamental questions concerning how iron homeostasis is regulated in mammals. Iron regulatory proteins (IRP) are critical regulators of mammalian iron metabolism that bind iron responsive elements (IRE) in target mRNA thereby controlling the uptake and metabolic fate of iron. At least six mRNA encoding proteins of diverse functions contain a single IRE in their 5'untranslated region allowing iron-dependent control of mRNA translation by IRP1 and IRP2. Dysregulation of IRP or the mRNA targets of IRP action, such as the heme formation enzyme erythroid 5'aminolevulinate synthase (eALAS), causes disease in humans and animal models of human disease. Although IRP are considered central regulators of mammalian iron metabolism and control the synthesis of proteins of widely differing function relatively little is known concerning how IRP selectively control the fate of IRE-containing mRNA. We propose to determine the individual roles of each IRP by elucidating the effect of altered iron status on the translation of 5'IRE-containing mRNA in mice lacking IRP1 or IRP2. Furthermore, we hypothesize that coordinate induction of IRP binding activity is required for the proper regulation of liver iron storage and export to support adequate rates of red cell formation. We further hypothesize that the well-known ability of liver to resist iron deficiency is dependent on adequate induction of IRP. We will test these hypotheses by determining the impact of iron deficiency on liver iron metabolism and on iron dependent functions. PUBLIC HEALTH RELEVANCE: Disorders of iron metabolism, whether caused by genetic errors, maladaptive response to disease, or diet are major public health issues affecting Americans. Iron regulatory proteins (IRPs) are critical components of a sensory and regulatory system that controls iron metabolism in key tissues including liver and their dysregulation of IRP action contributes to hematologic and neurologic diseases. This proposal focuses on elucidating the role of each IRP in the control of liver iron metabolism and function and its impact on the maintenance of whole body iron homeostasis.